The leachability and ecotoxicity of potentially toxic elements (PTE) eluting from technosols formed of soils affected by mining activities and limestone filler were evaluated. A total of four ...contaminated soils affected by opencast mining were selected and mixed with limestone filler at three percentages: 10, 20 and 30 %, providing 12 stabilised samples. Total and soluble PTE content (As, Cd, Cu, Fe, Pb and Zn) was determined in all the samples and the Microtox® bioassay was applied to determine the ecotoxicological effect. The stabilised material had a neutral pH and low soluble PTE concentration. Moreover, the ecotoxicological assay indicated the presence of low toxicity levels in the stabilised samples. The applied bioassay can be considered a good tool for the screening of PTE contamination in areas affected by mining activities, while providing information about possible attenuation processes.
This paper investigates the relationship between flexible human resource (HR) practices and innovativeness. Testing the research model in a sample of first‐tier automotive suppliers indicates that ...internal flexibility practices are positively related to innovativeness. Regarding external flexibility, the association depends on the type of contingent employee: negative association for ‘short‐term hires’ and positive association for ‘consulting/contracting firms’. The relationships to innovativeness for practices associated with knowledge transfer are moderated by environmental dynamism, but the non‐knowledge related practices are not. Firms in highly dynamic environments can benefit more from flexible HR practices than firms in less dynamic environments.
Background: There is evidence suggesting that CTCs are responsible for the spreading of clonal plasma cells (PC) inside and outside the bone marrow (BM). However, some pts unexpectedly have no CTCs ...at diagnosis. Here, we hypothesize that the absence of CTC defines a specific MM subtype with unique biological and clinical features. To our knowledge, this has never been investigated. Aim: Define the frequency and the characteristics of MM pts with undetectable CTCs. Methods: The presence of CTCs was assessed by NGF in 1,687 blood samples from pts with MGUS (n=467), smoldering (SMM, n=368), newly diagnosed (NDMM, n=652), and relapsed refractory MM (RRMM, n=200). All pts were enrolled in prospective PETHEMA/GEM multicenter studies. BM clonal PC from pts with (n=239) and without (n=17) detectable CTCs were isolated by FACS prior exome and RNA sequencing. Results: The frequency of pts with undetectable CTCs progressively decreased ( p <.001) from MGUS (54%) to SMM (21%) and NDMM (8%) and RRMM (11%). In those with detectable CTCs, the median percentage was 0.0003, 0.002, 0.01 and 0.008, respectively ( p <.001). The 1-log increment observed in the progression from MGUS to SMM and NDMM underpins the link between CTC levels and malignant transformation. The similarity between NDMM and RRMM is probably related with the fact that the latter were analyzed in between different lines of therapy. When compared to other SMM pts, those with undetectable CTCs were more frequently staged with low risk according to the 20/2/20 IMWG model (32% vs 49%; p <.001). Absence of CTCs (HR: 0.38; p =.042) and the 20/2/20 IMWG model (HR: 0.46; p =.011) had independent prognostic value in a multivariate analysis. SMM pts with undetectable vs detectable CTCs showed lower risk of transformation (progression rates at 2 years of 7% vs 24%, p =.004). When compared to other NDMM pts, those with undetectable CTCs had significantly less anemia and BM infiltration. There were no differences in the incidence of lytic lesions, renal insufficiency and hypercalcemia. Only one pt without CTCs was staged with R-ISS 3. These findings, together with a higher frequency of plasmacytomas, suggest that the MM subtype with undetectable CTCs may include pts with macrofocal disease. In transplant eligible NDMM, pts with undetectable vs detectable CTCs had PFS rates at 7 years of 90% and 44% (HR: 0.14; p <.001), and OS rates of 97% and 72% (HR: 0.10; p =.02). In transplant ineligible NDMM, pts with undetectable vs detectable CTCs had PFS rates at 2 years of 83% and 54% (HR: 0.31; p =.02), and OS rates of 94% and 76% (HR: 0.33; p =.13). In a multivariate analysis including the R-ISS and transplant eligibility, the absence of CTCs showed independent prognostic value for PFS (HR: 0.25; p <.001) and OS (HR: 0.24; p =.014). Among pts with undetectable CTCs, there were no differences in PFS and OS according to the presence of standard vs high risk cytogenetic abnormalities. In contrast with pts having detectable CTCs, the PFS and OS of those without CTCs was not significantly reduced if CR or MRD negativity were not achieved after treatment. The cytogenetic profile of BM clonal PC from pts with undetectable (n=112) vs detectable (n=846) CTCs was characterized by a lower frequency of +1q21 (16% vs 45%, p <.001) and del(1p32) (2% vs 8%, p =.02). Other alterations were not significant. There was no correlation between the number of mutations and the percentage of CTCs. There were 66 differentially expressed genes (DEG) between BM clonal PC from pts with detectable vs undetectable CTCs. Of note, 9 of the 66 DEG were in Chr1, with up- and downregulation of genes in 1p and 1q, respectively. There was a significant correlation between CTC levels and the expression of genes associated with MM dissemination ( FLNA , LGALS1and CXCR4). These findings, together with the modest correlation between the percentage of CTCs and BM clonal PC determined by morphology (r=.45, p <.001) and NGF (r=.49, p <.001), suggest that the selective egress of tumor cells from BM into the PB might depend on specific genetic alterations and transcriptional priming more than tumor burden. Conclusions:This study uncovered that ~8% of MM pts may progress due to mechanisms different from CTC dissemination. This subgroup showed unique features and achieved unprecedented outcomes, particularly if eligible to intensive therapy. Accordingly, our results endorse the recognition of pts with undetectable CTCs as a new biological and clinical subtype of MM.
Introduction: Chimeric antigen receptor (CAR) T-cell therapy fails to achieve durable responses in 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients in the third or later line ...setting. There is no standard treatment after CAR T-cell therapy progression and a wide range of outcomes are observed in this patient population. Besides the interval between CAR T-cell infusion and progressive disease (PD), data regarding prognostic factors at time of progression are scarce. Our aim was to develop a new prognostic tool to predict overall survival (OS) after CAR T-cell therapy progression with easily-available markers from routine clinical practice. Methods: First, we performed a retrospective data collection at 12 Spanish centers of R/R LBCL patients who progressed after CAR T-cell therapy in the third or later line setting from September 2018 until June 2022 (training cohort, TC). We analyzed a total of 15 variables, including pre-CAR T-cell therapy characteristics (gender, histology, primary refractory disease, previous hematopoietic transplant, number of previous lines) and values collected at time of progression to CAR T-cells (age, stage, extranodal sites, ECOG, hemoglobin, neutrophils, platelets, LDH, best response to CAR T-cells, time from CAR T-cell infusion to PD). The primary endpoint was OS from date of progression to CAR T-cell therapy. A stratified Cox model was used to estimate hazard ratios (HRs) using post-progression treatment as a stratification factor. We used LASSO regression with minimum lambda to identify which variables had the highest prognostic impact on OS. Additionally, the factors with a lower contribution were eliminated to create a parsimonious model. The C-statistic was used to evaluate its discrimination. We examined the performance of the International Prognostic Index (IPI) score and Revised IPI (R-IPI) in this setting. Finally, we tested the score in an external validation cohort (VC) which included a comparable patient population from 3 European countries. Results: Among the 216 LBCL patients included in the TC, most were male (66%), had an ECOG of 1 (48%) and stage IV disease (71%) at time of CAR T-cell therapy progression. Median time from CAR T-cell infusion to PD was 2.5 months (95CI% 1.9-2.9) and median follow-up from progression was 15 months. Salvage treatment was classified into 3 subgroups, including immunotherapy or targeted agents (43%), chemotherapy or radiotherapy (20%) and palliative care (38%). To build the prognostic score, a total of 5 variables were selected. Each marker received 1 point (given the similar HR 1.48-1.77), if they met defined criteria: ECOG (>0), hemoglobin (<10 g/dL), LDH (>2 x upper normal limit), number of extranodal sites (>1) and time from CAR T-cell infusion to PD (<4 months). Patients with 0-1 points were classified as low risk, 2 points as intermediate-low risk, 3 points as intermediate-high risk and 4 or 5 points as high risk. In the TC, the 4 risk groups showed statistically significant differences in OS (Figure 1). In the low-risk group (n=39 18%), the median OS mOS was not reached; in the intermediate-low risk (n=56 26%) mOS was 7.3 months (HR=2.89, p=0.002); in the intermediate-high risk (n=57 26%) mOS was 4.9 months (HR=4.81, p<0.001) and in the high risk (n=64 30%) mOS was 1.8 months (HR=6.69, p<0.001). In terms of post-relapse therapies, both the chemo/radiotherapy and the immunotherapy groups showed a balanced patient distribution, from low to high risk (32%, 35%, 14% and 19% vs 22%, 32%, 30% and 16%, respectively). The VC included 204 patients with a similar patient distribution in the 4 prognostic risk groups (35%, 25%, 12%, 27%). The mOS for each of these groups was 15.2, 5.3, 2.9 and 0.9 months, respectively. Each group had distinct OS outcomes when compared with all the other risk groups (p<0.05 for each comparison) (Figure 2). Finally, our model presented a C-index of 0.712 for the TC and 0.811 for the VC, outperforming both the IPI (0.647 TC and 0.691 VC) and R-IPI (0.632 TC and 0.683 VC). Conclusions: The Post-CAR Prognostic Index (PC-PI) is a clinically useful tool for OS prediction and risk-adapted treatment planning in LBCL patients progressing after CAR T-cell therapy. In addition, our results will help stratification in clinical trials which include patients with prior CAR T-cell therapy.
Smoking is an established risk factor for pancreatic cancer, previously investigated by the means of questionnaires. Using cotinine as a biomarker for tobacco exposure allows more accurate ...quantitative analyses to be performed. This study on pancreatic cancer, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC cohort), included 146 cases and 146 matched controls. Using liquid chromatography‐mass spectrometry, plasma cotinine levels were analyzed on average 8.0 years before cancer onset (5–95% range: 2.8–12.0 years). The relation between plasma cotinine levels and pancreatic cancer was analyzed with conditional logistic regression for different levels of cotinine in a population of never and current smokers. This was also done for the self‐reported number of smoked cigarettes per day at baseline. Every increase of 350 nmol/L of plasma cotinine was found to significantly elevate risk of pancreatic cancer odds ratio (OR): 1.33, 95% confidence interval (CI): 1.11–1.60. People with a cotinine level over 1187.8 nmol/L, a level comparable to smoking 17 cigarettes per day, have an elevated risk of pancreatic cancer, compared to people with cotinine levels below 55 nmol/L (OR: 3.66, 95% CI: 1.44–9.26). The results for self‐reported smoking at baseline also show an increased risk of pancreatic cancer from cigarette smoking based on questionnaire information. People who smoke more than 30 cigarettes per day showed the highest risk compared to never smokers (OR: 4.15, 95% CI: 1.02–16.42). This study is the first to show that plasma cotinine levels are strongly related to pancreatic cancer.
Abstract A western lifestyle, characterised by low rates of energy expenditure and a high-energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high ...incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk.
Introduction. Autologous chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). Real-world studies have ...reported improved outcomes in terms of safety and efficacy in comparison with pivotal trials. These differences have been associated to a learning curve in patient selection and adverse event control, but this hypothesis has not been proven. The aim of this study was to analyze patient selection and CAR T-cell management across different time periods and assess its impact on treatment outcomes Methods. This retrospective analysis included all consecutive LBCL patients receiving CAR-T cell therapy (axicabtagene-ciloleucel axi-cel and tisagenlecleucel) in the third line setting from approval in 2019 to 2023 and reported in the Spanish Registry. Patients were categorized in 3 consecutive time periods of 18 months each according to infusion date. Baseline characteristics, manufacturing times and production failures as well as efficacy and safety outcomes were compared across periods. An additional safety and efficacy analysis was conducted in patients receiving axi-cel. Results. The study included 458 patients: 117 (26%), 194 (42%) and 147 (32%) in the early (EP) (January 2019-June 2020), intermediate (IP) (July 2020-December 2021) and recent period (RP) (January 2022-June 2023), respectively. In terms of patient profile, baseline characteristics evolved overtime as patients in the RP had received less number of prior therapies, had less primary refractory disease, less bulky disease and had lower LDH at lymphodepletion. On the contrary, the RP had more patients with ECOG performance status ³2 and higher comorbidity burden. Regarding the product, the use of axi-cel increased overtime, from 45% in the EP to 83% in the RP (Table). The time from apheresis to infusion improved overtime, moving from 48 days in the EP to 38 days in the RP. Manufacturing failures (5%) and use of bridging therapy (81%) remained stable overtime. Regarding efficacy, overall (complete) response rates improved overtime (from 66% 25% in the EP to 78% 52% in the RP p<0.001, respectively). Median PFS and OS for the whole cohort were 3.9 months (95% CI 3.23-5.83) and 18.5 months (95% CI 13.53 - 27.67) without differences across periods. In terms of toxicity, patients in the RP had more grade > or = 3 CRS and ICANS, received more tocilizumab and corticosteroids and required more ICU admission compared with the EP. These results were driven by the higher use of axi-cel in the RP. When focusing exclusively on axi-cel patients (n=301), the CR rate also improved overtime (32% in the EP; 37% in the IP and 55% in the RP, p=0.016) (Figure) while median PFS (6.63 months, 95%CI 3.90 - 11.43) and OS (25.73 months, 95%CI 18.57 - NA) remained stable. In the multivariable analysis, ECOG PS > 1 (HR 2.68, 95% CI 1.35-5.09, p=0.005) and LDH ³ 500 UI/L (HR 1.54, 95% CI 1.02-2.31, p=0.04) but not treatment period were associated with a shorter PFS. In terms of toxicity, the time to CRS onset (median of 3 vs. 1 days, p=0.001) and ICANS (median of 8 vs. 6 days, p=0.06) was later in the EP compared with the RP. The incidence of grade > or = 3 CRS and ICANS (ranging from 10% to 7% and 36% to 41%, respectively), the use of tocilizumab, corticosteroids, and anakinra as well as ICU admission rate and 12-month non-relapse mortality (2% vs 5%) remained stable across periods. Conclusion. The criteria for selecting patients for CAR T-cell therapy have evolved overtime towards a less aggressive disease profile and allowing less fit patients for therapy in recent times. Patients treated in the RP were more likely to respond to these therapies but this did not translate into prolonged survival or an improved safety profile.
Coastal lagoons are among the marine habitats with the highest biological productivity, and supports a great variety of human activities and pressures that makes them especially vulnerable to trophic ...imbalances. While dystrophic crises are common in many lagoons, others like the Mar Menor show homeostatic mechanisms, high resilience and clear waters. This paper analyses the water column descriptors dynamic during the last 22 years in this lagoon, in the context of a eutrophication process produced by an increase in nutrient inputs, mainly derived from agriculture. Despite the increase in nitrate loads, the lagoon maintained two decades of homeostatic regulation, keeping the water transparency and relatively low levels of nutrients and chlorophyll a (Prebreak phase), followed by a sudden change of state in 2016 with an abrupt increase in nutrients and chlorophyll a concentration and loss of water transparency (Break phase), and a relatively rapid recovery after the reduction of nutrient discharges (Recovery phase). The activation of the regulation mechanisms is manifested by an ammonium production, as a consequence of the trophic web activity. The low relationship between chlorophyll and nutrients, mainly at small spatio-temporal scales, disagrees with the eutrophication traditional models, suggesting a rapid response of primary producers to nutrient inputs and a zooplankton control in the short-term, which in turn is controlled by the rest of the trophic web components. Homeostatic properties that provide resistance to the Mar Menor lagoon to deal with eutrophication are based on several mechanisms: channelling its production towards the benthic system (maintaining high biomasses of primary producers, filter feeders and detritivores), a top-down control of the pelagic trophic web exerted by ichthyoplankton and jellyfish, and exporting surplus production outside the system. Resilience of the system would be based on the high turnover in the species composition related to the restricted connectivity with the sea, the spatio-temporal variability of the environmental conditions, and the multiplicity of spatial-temporal scales involved in lagoon processes. TRIX index was sensitive to the water quality changes. However, in our study, its current score does not allow to anticipate or alert the eutrophication risk and the trophic breakpoint of the system.
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